Project summary Perturbations in the kynurenine pathway metabolites have been associated with alterations in glutamate, acetylcholine, serotonin and dopamine signaling, and have been linked to schizophrenia. During the first 5 year of the Conte project, we have developed new evidence that kynurenergic effects in schizophrenia maybe dynamically related to stress response and genetics. Identifying the underlying mechanism would be critical to determine whether this pathway is critical in schizophrenia and how it is related to the known pathophysiological glutamate, acetylcholine, serotonin and dopamine signaling in this illness. The downstream substrates of the tryptophan-kynurenine mechanism involve multiple and frequently opposite actions. Although many of these actions have implications in schizophrenia, the field lacks a coherent schizophrenia-kynurenine model, hindering meaningful preclinical-clinical translations. The difficulty may be due to the inherent complexity of the system and its interactions with genetics and developmental risk factors. We will employ a combination of cellular to patient ex-vivo cellular genetic approaches to analyze the role genetic effects on the kynurenine pathway signaling in schizophrenia. The empahsis is on stress-induced kynurenergic response and its associated brain circuitry and glutamatergic signaling biomarkers. The project is ambitious and translational, involving clinical, brain imaging, and cellular models for specific genetic effects. However, we have formed a strong, highly integrated team and project design, and the preliminary studies support our proposed specific aims, demonstrate feasibility, and suggest a significant potential for novel discoveries if these aims are supported in the proposed studies. Knowledge on how the kynurenine pathway is involved in clinical schizophrenia patients will lead to more specific and better treatment targets for drug development.